Hydrogels have been considered as promising materials for controlled delivery of macromolecular therapeutics such as proteins, peptides, and genes, due to their good biocompatibility and tunable mechanical and chemical properties. However, the high water content of hydrogels generally results in a rapid release of macromolecular therapeutics (typically a few hours) with a large burst release. Burst release of therapeutics not only decreases the efficiency of the therapy but also can cause serious side effects due to the sudden increase of drug concentration in the blood. In addition, efficient loading of macromolecular therapeutics to the hydrogels is challenging. While adding therapeutics into the hydrogel preparation solution is straightforward, this method generally results in low loading yield due to release of therapeutics during hydrogel cleaning (washing) steps. Also, some hydrogel preparation methods, including heating and/or sonication, can denature or degrade these biomolecules. Alternatively, macromolecular therapeutics can be loaded to the hydrogels after synthesis by passive diffusion of the proteins into the polymer network. However, rapid release of proteins with a large burst release is often observed for this approach. To overcome these limitations, recently, several other strategies such as photo-crosslinking, physical crosslinking, and addition of drug-laden microparticles have been reported; however, in only a few of these studies were good loading yield and sustained and burst-free release profiles achieved. Therefore, development of alternative hydrogel formulations to address the aforementioned limitations in hydrogel-based macromolecular therapeutic delivery platforms is still needed.